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Cholecystokinin Receptor Antagonist Therapy Decreases Inflammation and Fibrosis in Chronic Pancreatitis

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Abstract

Background and Aims

Chronic pancreatitis is associated with recurrent inflammation, pain, fibrosis, and loss of exocrine and endocrine pancreatic function and risk of cancer. We hypothesized that activation of the CCK receptor contributes to pancreatitis and blockade of this pathway would improve chronic pancreatitis.

Methods

Two murine models were used to determine whether CCK receptor blockade with proglumide could prevent and reverse histologic and biochemical features of chronic pancreatitis: the 6-week repetitive chronic cerulein injection model and the modified 75% choline-deficient ethionine (CDE) diet. In the CDE-fed model, half the mice received water supplemented with proglumide, for 18 weeks. After chronic pancreatitis was established in the cerulein model, half the mice were treated with proglumide and half with water. Histology was scored in a blinded fashion for inflammation, fibrosis and acinar ductal metaplasia (ADM) and serum lipase levels were measured. RNA was extracted and examined for differentially expressed fibrosis genes.

Results

Proglumide therapy decreased pancreatic weight in the CDE diet study and the cerulein-induced chronic pancreatitis model. Fibrosis, inflammation, and ADM scores were significantly reduced in both models. Lipase values improved with proglumide but not in controls in both models. Proglumide decreased pancreas mRNA expression of amylase, collagen-4, and TGFβR2 gene expression by 44, 38, and 25%, respectively, compared to control mice.

Conclusion

New strategies are needed to decreased inflammation and reduce fibrosis in chronic pancreatitis. CCK receptor antagonist therapy may improve chronic pancreatitis by reversing fibrosis and inflammation. The decrease in ADM may reduce the risk of the development of pancreatic cancer.

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Abbreviations

ADM:

Acinar ductal metaplasia

CCK:

Cholecystokinin

CDE:

Choline-deficient ethionine

MMP:

Matrix metalloproteinase

PSC:

Pancreatic stellate cells

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Acknowledgments

We appreciate the technical support from the staff in the Lombardi Core Histology laboratory. We also appreciate the staff in the animal care facility.

Funding

This work was funded by a grant from the National Pancreas Foundation to SN and VC. Part of the work was also funded by an American Gastroenterology Association Elsevier Pilot Research Award to JPS. Postdoctoral support was provided by a NIH training grant to Sandeep Nadella TL1TR001431. These studies were conducted in part at the Lombardi Comprehensive Cancer Center Histopathology and Tissue Shared resource and in the Preclinical Imaging Research Laboratory which is supported in part by NIH/NCI grant P30-CA051008.

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Author notes

  1. Sandeep Nadella and Victor Ciofoaia have contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Georgetown University, 4000 Reservoir Rd, NW, Building D, Room 338, Washington, DC, 20007, USA

    Sandeep Nadella, Victor Ciofoaia, Hong Cao & Jill P. Smith

  2. Department of Pathology, Georgetown University, Washington, DC, USA

    Bhaskar Kallakury & Robin D. Tucker

  3. Mayo Clinic, Rochester, MN, USA

    Victor Ciofoaia

Authors
  1. Sandeep Nadella
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  2. Victor Ciofoaia
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Contributions

SN, VC, and JPS contributed to conception and design; SN, VC, HC, BK, RDT, and JPS contributed to acquisition of data; analysis and interpretation of data (e.g., statistical analysis, biostatistics, and computational analysis) were performed by SN, VC, HC, and JPS; all authors contributed equally to writing, review, and/or revision of the manuscript.

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Correspondence to Jill P. Smith.

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Nadella, S., Ciofoaia, V., Cao, H. et al. Cholecystokinin Receptor Antagonist Therapy Decreases Inflammation and Fibrosis in Chronic Pancreatitis. Dig Dis Sci 65, 1376–1384 (2020). https://doi.org/10.1007/s10620-019-05863-5

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  • DOI: https://doi.org/10.1007/s10620-019-05863-5

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